It is generally assumed that benzimidazoles such as omeprazole are unstable in an acidic environment and that, for this reason, pharmaceutical formulations comprising such a benzimidazole ought to comprise an alkaline reacting compound. One example of such a formulation is described in EP-A 0 247 983.
It is possible by combining the benzimidazoles with a sufficient quantity of alkaline reacting compound to obtain pharmaceutical formulations having quite good stability. However, pharmaceutical formulations of this type have intrinsic problems. For example, acidic groups are present in the enteric coating of the formulations and are able to react with the alkaline reacting compound of the core. Whereas it is well known to separate the alkaline reacting core from the enteric coating by an intermediate layer, great care must be applied during the production of such pharmaceutical formulations in order to adjust the thickness and nature of the intermediate layer and the nature of the enteric coating to the alkalinity of the core so that a pharmaceutical formulation with adequate stability and good bioavailability is obtained. Problems of this type are discussed, for example, in example 1 of EP-A 0 247 983.
Some formulations in which the benzimidazole is not combined with an alkaline reacting compound have recently been developed. One example of such a development is described in U.S. Pat. No. 5,626,875, corresponding to EP-A 0 773 025. This publication discloses a formulation comprising                an inert core,        which is coated with a first layer which comprises the benzimidazole together with a water-soluble polymer,        a further layer comprising a water-soluble polymer and        an enteric coating.        
In the examples of this publication, the benzimidazole is formulated with excipients which are generally regarded as inert, such as, for example, talc. Talc in pharmaceutical quality may, however, contain impurities, and a pH of more than 7 is often measured in a suspension of talc in water (ISFET technique for phenol red indicator).
Several recently developed omeprazole-containing pharmaceuticals combine omeprazole with a specific stabilizer in order to increase the stability of the composition, such as, for example, mannitol (EP-A 646 006), TiO2 (WO 96/37195) or cyclodextrins (WO 98/40069) or amino acids. However, it would be desirable to have available an omeprazole-containing pharmaceutical which is sufficiently stable without such a stabilizer.
There is a need for pharmaceuticals which comprise benzimidazole compounds and, in particular, omeprazole or a similar compound as active ingredient, which have an excellent stability combined with good bioavailability, and which do not show the problems and disadvantages of some prior art pharmaceuticals.
The present invention is based on the unexpected finding that the benzimidazoles which have been regarded as very acid-labile in fact have an excellent stability when they are formulated together with a compound which provides a pH of less than 7 if they are brought into contact with sufficient water in order to measure a pH (acidic reacting compound, acidic substance).